The Pacific Northwest is a unique and critical location for study of shellfish associated exposure to domoic acid, because there are many groups of diverse and high levels consumers of seafood in this region where domoic acid shellfish contamination is a common phenomenon (currently causing closure of a Washington crab and razor clam fishery). Over forty tribal nations are present in the Pacific Northwest, each with members with very different shellfish consumption patterns. Studies with some of these groups have already revealed that average shellfish consumption exceeds the 95 th percentile of U.S. shellfish consumption, however details of consumption for tribes with close proximity to shellfish containing the highest domoic acid concentrations and slowest depuration rates are largely unknown. In addition, there are large Asian and Pacific Islander (API) communities including Koreans, Samoans, Hmong, Vietnamese, Japanese, Cambodians, Mien, Chinese, and others in the Puget Sound area, where domoic acid has also been detected. In both tribal and API communities, cultural practices and habits result in consumption behaviors, like drinking shellfish cooking water and consumption of the crab hepatopancreas, which may make them more vulnerable to both acute high level and chronic low-level exposure to domoic acid. Our Center researchers have established relationships with these groups (see letters of support) and will partner with two API communities (one Japanese and one Indochinese community) and three west coast tribes (Quileute, Quinault, and Makah). There is growing evidence both from animal and human studies that the young and the elderly may be at increased risk for domoic acid neurodevelopmental and neurobehavioral insult. In preliminary studies with the Quileute tribe, Center collaborator Lynn Grattan has observed neurobehavioral effects from domoic acid exposure in infants and children. Thus exposure studies and risk assessments need to consider many exposure and risk factors (location, preparation, diet, and seasonality, age, antioxidants, and co-exposures) to assess aggregate exposure and risk. The human exposure studies that we propose in this Center will provide the link between the Center's basic research on mechanisms of toxicity and environmental domoic acid contamination. Unique opportunities exist for developing mechanistic based risk evaluation for humans for both acute and chronic exposure scenarios by extrapolating results from the Mechanisms of Toxicity Project. The use of molecular mechanism based models and risk assessment modeling approaches will allow direct testing of the hypothesis that age, genetics, and diet are key susceptibility factors.